AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol.
AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol.
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DOI：
10.1016/j.freeradbiomed.2011.08.002
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发表时间：
2011-11-01
影响因子：
7.4
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Ge, Wei;Guo, Rui;Ren, Jun
线粒体醛脱氢酶-2 （ALDH2）减轻乙醇毒性，但其确切机制尚不清楚。本研究旨在评估ALDH2对乙醇诱导心肌自噬损伤的影响。用乙醇（3 g/kg/d, i.p）刺激过表达ALDH2的野生型FVB和转基因小鼠3天，利用超声心动图和IonOptix系统评估心脏力学功能。Western blot分析细胞自噬的基本标志物Akt和AMPK及其下游信号mTOR。乙醇刺激改变了心脏的几何形状和功能，心室收缩和舒张末期直径增大，细胞缩短和细胞内Ca2+升高减少，细胞内Ca2+衰减延长，以及SERCA Ca2+摄取减少，这些影响被ALDH2减轻。乙醇刺激可促进心肌自噬，Beclin、ATG7和LC3B II的表达增强，mTOR去磷酸化，ALDH2可减轻这一作用。ALDH-2激动剂Alda-1、自噬抑制剂3-MA和AMPK抑制剂化合物C可逆转乙醇刺激诱导的心脏缺损和细胞凋亡，而自噬诱导剂雷帕霉素和AMPK激活剂AICAR可模拟或加重乙醇诱导的细胞损伤。乙醇在FVB小鼠心脏中分别促进或抑制AMPK和Akt的磷酸化，但对ALDH2没有作用。此外，AICAR使alda -1诱导的对乙醇引发的自噬和功能变化的保护失效。乙醇使H9c2细胞中GFP-LC3斑点增加，Alda-1和3-MA消除了这种作用。使用巴菲霉素A1、E64D和胃抑素A抑制溶酶体可消除Alda-1，但不影响乙醇诱导的GFP-LC3点的反应。我们的研究结果表明，ALDH2通过改变Akt和AMPK信号以及调节自噬通量来保护乙醇毒性。
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) alleviates ethanol toxicity although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on ethanol-induced myocardial damage with a focus on autophagy. Wild-type FVB and transgenic mice overexpressing ALDH2 were challenged with ethanol (3 g/kg/d, i.p.) for 3 days and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate essential autophagy markers, Akt and AMPK and their downstream signaling mTOR. Ethanol challenge altered cardiac geometry and function evidenced by enlarged ventricular end systolic and diastolic diameters, decreased cell shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay, as well as reduced SERCA Ca2+ uptake, the effects of which were mitigated by ALDH2. Ethanol challenge facilitated myocardial autophagy as evidenced by enhanced expression of Beclin, ATG7 and LC3B II, as well as mTOR dephosphorylation, which was alleviated by ALDH2. Ethanol challenge-induced cardiac defect and apoptosis were reversed by the ALDH-2 agonist Alda-1, the autophagy inhibitor 3-MA, and the AMPK inhibitor compound C whereas the autophagy inducer rapamycin and the AMPK activator AICAR mimicked or exacerbated ethanol-induced cell injury. Ethanol promoted or suppressed phosphorylation of AMPK and Akt, respectively, in FVB but not ALDH2 murine hearts. Moreover, AICAR nullified Alda-1-induced protection against ethanol-triggered autophagic and functional changes. Ethanol increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by Alda-1 and 3-MA. Lysosomal inhibition using bafilomycin A1, E64D and pepstatin A obliterated Alda-1- but not ethanol-induced responses in GFP-LC3 puncta. Our results suggested that ALDH2 protects against ethanol toxicity through altered Akt and AMPK signaling and regulation of autophagic flux.
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影响因子：
2.3
作者：
Ren, Jun;Wold, Loren E
通讯作者：
Wold, Loren E
影响因子：
20.1
作者：
Gustafsson AB;Gottlieb RA
通讯作者：
Gottlieb RA
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37.8
作者：
Koda K;Salazar-Rodriguez M;Corti F;Chan NY;Estephan R;Silver RB;Mochly-Rosen D;Levi R
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Levi R
影响因子：
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作者：
Ma, Heng;Li, Ji;Ren, Jun
通讯作者：
Ren, Jun
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Li, SY;Li, Q;Ren, J
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